This invention pertains to an osmotic device containing ranitidine. More particularly, it pertains to an osmotic device tablet which provides a controlled release of ranitidine and a prokinetic agent, following a particularly advantageous release profile.
Gastroesophageal reflux disease (GERD), reflux oesophagitis, peptic ulcer, gastric ulcer and other gastric acid related disorders are disorders having a pathogenesis related to reduced gastric motility, i.e., reduced clearing capacity of the stomach, and release of excessive gastric acid. Aside from behavioral changes, GERD and gastric ulcer have been successfully treated with a range of gastric acid inhibitors, such as ranitidine and omeprazole, which are known as H2 blocker or acid-suppressing drugs. Stimulation of gastric motility has been proposed to accelerate the healing of gastric ulcer. Prokinetic drugs, such as cisapride, are known to enhance gastrointestinal motility and prevent duodenogastric reflux, and are widely used to treat GERD. Ranitidine and prokinetic drugs have been used in combination to treat gastric ulcer and other related disorders.
Ranitidine is commercially available in tablet, liquid and capsule dosage forms from Geneva Farms, Glaxo Wellcome (Zantac(trademark)), Boehringer Ingelheim, Mylan, Novopharm N.C., Ranbaxy, Torpharm, Wockhardt and Zenith Goldline. The tablets and capsules are available in 150 and 300 mg strengths.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No. 6,004,582to Faour et al., and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference.
These references, however, do not disclose osmotic devices that provide the specific plasma profiles or release profiles for ranitidine (RNT) that the present invention provides. Moreover, the prior art does not disclose an osmotic device containing a combination of ranitidine with a prokinetic agent, wherein the ranitidine and prokinetic agent are provided according to specific release profiles.
The osmotic devices of the present invention seek to overcome the disadvantages found in known ranitidine formulations. These osmotic devices provide improved therapeutic benefits over conventional devices.
In one aspect, the present invention provides an osmotic device comprising:
a core comprising a therapeutically effective amount of ranitidine and at least one osmotic agent or osmopolymer; and
a semipermeable membrane surrounding the core and having a passageway there through;
wherein the core provides a controlled release of RNT, and at least 60% of the RNT is released within 20 hours after exposure of the osmotic device to an aqueous solution.
Another aspect of the present invention provides an osmotic device for delivering ranitidine and a prokinetic agent comprising:
a core comprising a therapeutically effective amount of ranitidine and at least one osmotic agent or osmopolymer;
a semipermeable membrane surrounding the core and having a passageway there through; and
an external coat comprising a therapeutically effective amount of a prokinetic agent and ranitidine;
wherein the core provides a controlled release of RNT, and at least 60% of the RNT is released from the core within 20 hours after exposure of the osmotic device to an aqueous solution, and the external coat provides a rapid release of the prokinetic agent, and at least 75% of the prokinetic agent is released within 1 hour and 80% of RNT in the external coat is released within 1 hour after exposure of the osmotic device to an aqueous solution.
In still other preferred embodiments, the external coat is applied by spray-coating or compression-coating. By spray coating rather than compression coating the external coat, a thinner external coat, and therefore a smaller osmotic device, is formed.
Another aspect of the invention provides a method of treating a gastric acid related disorder in a mammal. This method comprises the step of administering an osmotic device, which provides a controlled release of RNT from its core and a rapid release of a prokinetic agent and RNT from an external coat and RNT, wherein at least 75% of the prokinetic agent is released within about 40 minutes, and at least about 75% of the RNT in the external coat is released within about 1 hour after administration. Gastric acid-related disorders include, for example, gastric ulcer, peptic ulcer, GERD (gastroesophageal reflux disease), and reflux esophagitis.
In other preferred embodiments, the osmotic device provides: a) an RNT release profile similar to that shown in any of FIGS. 1-3; or b) an osmotic device made according to example 1. In still other preferred embodiments, the release of RNT and/or the prokinetic agent has a delayed onset.
In still other preferred embodiments, the prokinetic agent is selected from the group consisting of cisapride, mosapride, domperidone and clevopride.
The osmotic device generally delivers the prokinetic agent to the upper GI tract and the ranitidine to the middle to lower GI tract.
The device can be tailored for once or twice daily administration. The amounts of ranitidine and prokinetic agent can be varied. One embodiment provides two different charges of ranitidine (one rapid release and the other controlled release) and a rapid release charge of prokinetic agent. This embodiment rapidly provides the therapeutic benefit of both drugs so that gastric discomfort is relieved shortly after administration.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples.